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| United States Patent |
5,653,993
|
|
Ghanta
, et al.
|
August 5, 1997
|
Procedure for encapsulating ibuprofen
Abstract
This disclosure is directed to preparation of individual taste-masked, high
bioavailability, high payload, microcapsules by microencapsulation of
water-insoluble NSAID drug materials in the substantial absence of
microcapsule agglomerates. These taste-masked microcapsules contain a high
payload, e.g., about 83+wt. % of said NSAID drug material having high
bioavailability and can then be formulated into chewable tablets and
liquid aqueous suspensions for medicinal use. Both cellulose acetate
phthalate and gelatin are the microencapsulating polymer wall material.
Control of pH, controlled addition of a Hofmeister (lyotropic) salt,
microencapsulation of the water-insoluble NSAID medicament with a liquid
phase of both cellulose acetate phthalate and gelatin microencapsulating
material and the subsequent insolubilization of said liquid encapsulating
material after it is wrapped around the medicament core with dilute acid
are important process parameters to achieving the proper individual
microcapsules to obtain highly bioavailability taste-masked,
water-insoluble NSAID drug materials, esp., naproxen and ibuprofen, by
microencapsulation alone.
| Inventors:
|
Ghanta; Sambasiva Rao (Centerville, OH);
Guisinger; Robert Edmon (Dayton, OH)
|
| Assignee:
|
Eurand America, Inc. (Vandalia, OH)
|
| Appl. No.:
|
483909 |
| Filed:
|
June 7, 1995 |
| Current U.S. Class: |
424/440; 424/451; 424/456 |
| Intern'l Class: |
A61K 009/48 |
| Field of Search: |
424/489,470,480,490,440,451,456
|
References Cited
U.S. Patent Documents
| 4460563 | Jul., 1984 | Calanchi | 424/35.
|
| 4462982 | Jul., 1984 | Samejima et al. | 424/35.
|
| 4766012 | Aug., 1988 | Valenti | 427/213.
|
| 4835186 | May., 1989 | Reuter | 514/570.
|
| 4835187 | May., 1989 | Reuter | 514/570.
|
| 4835188 | May., 1989 | Ho | 514/570.
|
| 4937254 | Jun., 1990 | Sheffield et al. | 424/497.
|
| 4952402 | Aug., 1990 | Sparks et al. | 424/470.
|
| 5215755 | Jun., 1993 | Roche et al. | 424/480.
|
Other References
H.P. Merkle et al "Preparation and In Vitro Evaluation of Cellulose Acetate
Phthalate Coacervate Microcapsules", J. Pharm. Science 62 pp. 1444-1448
(1973).
J.R. Nixon et al "The In Vitro Evaluation of Gelatin Coacerrate
Microcapsules", J. Pharm Pharmac, 1971, 23 Suppl. 1475-1555.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Benston; W.
Attorney, Agent or Firm: Routh; John W.
Parent Case Text
This is a continuation of application Ser. No. 08/106,024 filed on Aug. 13,
1993, now abandoned.
Claims
We claim:
1. A taste masked, microencapsulated, nonsteroidal, anti-inflammatory,
water-insoluble NSAID drug material comprising individual microcapsules
consisting essentially of NSAID drug particles and simultaneously
coacervated cellulose acetate phthalate and gelatin microencapsulating
wall materials having a high payload of active drug and characterized as
free flowing, individual, taste-masked microcapsules in the substantial
absence of microcapsule agglomerates and having a microcapsule particle
size distribution ranging from about 25 to about 600 microns.
2. A taste-masked microencapsulated water-insoluble NSAID drug material as
in claim 1 wherein said drug is naproxen.
3. A taste-masked microencapsulated water-insoluble NSAID drug material as
in claim 1 wherein said drug is ibuprofen.
4. A taste-masked microencapsulated water-insoluble NSAID drug material as
in claim 1 wherein said payload of active drug is about 83+wt. %.
5. A taste masked, microencapsulated, water-insoluble, non-steroidal,
anti-inflammatory drug (NSAID) in chewable tablet form containing
microcapsules as in claim 1 and pharmaceutically acceptable excipient
materials.
6. Chewable tablets as in claim 5 wherein said water-insoluble NSAID drug
material is naproxen.
7. Chewable tablets as in claim 5 wherein said water-insoluble NSAID drug
material is ibuprofen.
8. Chewable tablets as in claim 5 wherein the individual microcapsule
payload of active water-insoluble NSAID drug material is about 83+wt. %.
9. A liquid suspension comprising individual taste-masked microcapsules as
in claim 1 and pharmaceutically acceptable excipient materials.
10. A liquid suspension as in claim 9 wherein said water-insoluble NSAID
drug material is naproxen.
11. A liquid suspension as in claim 9 wherein said water-insoluble NSAID
drug material is ibuprofen.
12. A liquid suspension as in claim 9 wherein the individual microcapsule
payload of active water-insoluble NSAID drug material is about 83+wt. %.
13. A taste-masked microencapsulated water insoluble NSAID drug material as
in claim 1.
Description
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to preparation of individual
taste-masked, high bioavailability, high payload, microcapsules by
simultaneous micro-encapsulation of water-insoluble NSAID drug materials
in the substantial absence of microcapsule agglomerates. These
taste-masked microcapsules contain a high payload, e.g., about 83+ wt. %
of said NSAID drug material having high bioavailability and can be
formulated into chewable tablets and liquid aqueous suspensions for
medicinal use. Both cellulose acetate phthalate and gelatin are the
micro-encapsulating polymer wall materials.
Control of pH, controlled addition Of a Hofmeister (lyotropic) salt,
microencapsulation of the water-insoluble NSAID medicament with a liquid
phase of both cellulose acetate phthalate and gelatin microencapsulating
material, and the subsequent insolubilization of said liquid encapsulating
material after it is wrapped around the medicament core with dilute acid
and crosslinking agent are important process parameters to achieving the
proper individual microcapsules to obtain highly bioavailable,
taste-masked, water-insoluble NSAID drug materials, e.g., naproxen and
ibuprofen, by microencapsulation alone.
BACKGROUND OF THE INVENTION AND PRIOR ART
Non-steroidal anti-inflammatory drugs (NSAID) having analgesic and
anti-inflammatory properties have been widely administered orally in the
treatment of mild to severe pain, particularly for rheumatoid arthritis
and osteoarthritis patients. Tolerance or addiction to these drugs is not
generally a problem with their continuous use in the treatment of pain or
in the treatment of acute or chronic inflammatory states. However, these
drugs generally have a higher potential for adverse side effects at the
upper concentrations (limits) of their effective dose ranges. Therefore,
it is important that such non-steroidal anti-inflammatory drugs be
accurately measured and administered orally.
These non-steroidal anti-inflammatory drugs, e.g., ibuprofen and naproxen,
have been widely prescribed by physicians. These drugs are in general
tolerated well by most patients and provide an effective means for control
of pain and inflammatory processes, particularly for the rheumatoid
arthritis and osteoarthritis patients. However, these non-steroidal
anti-inflammatory drugs impart a burning sensation, have a bitter taste
and aftertaste, and/or have an adverse mouth feel when taken orally.
Therefore, in order to make wider use of them while substantially
eliminating the bitter taste, aftertaste and adverse mouth feel and make
these drugs more pleasant upon taking them orally, there has long been
desired a way to insure delivery of these drugs in their desired
concentrations while avoiding their extremely bitter taste, lingering
aftertaste and adverse mouth feel effects referred to above connected with
their ingestion orally, thereby encouraging patient compliance.
Various ways and delivery systems have been attempted in the prior art to
accomplish these and other objectives.
One such system is described in co-pending application of Thomas C. Powell
and Massimo M. Calanchi Serial No. 819,609, filed Jan. 9, 1992 and
entitled "Microencapsulated Taste-Masked Water Insoluble NSAID Drug
Materials". That application is directed to preparation of individual
taste-masked, high payload, microcapsules by microencapsulation of
water-insoluble NSAID drug materials in the substantial absence of
microcapsule agglomerates. These taste-masked microcapsules contain a high
payload, e.g., about 83+ wt. % of said NSAID drug material and can be
formulated into chewable tablets and liquid aqueous suspensions for
medicinal use. Cellulose acetate phthalate is the sole micro-encapsulating
polymer wall material.
Another such system is described by J. R. Nixon et al in an article
entitled "The In Vitro Evaluation of Gelatin Coacervate Microcapsules"
appearing in J. Pharm. Pharmac, 1971, 23 Suppl. 147S-155S. This article
describes the microencapsulation of sulfadiazine with gelatin using sodium
sulphate as the coacervation agent. The free flowing microcapsular
material was hardened with formalin, although other hardening agents such
as glutaraldehyde and acrolein could be used as cross linking agents. In
vitro dissolution studies were carried out.
U.S. Pat. No. 4,766,012, issued to Valenti, teaches the microencapsulation
of ibuprofen and naproxen. The microencapsulation method employed by
Valenti involves dissolving a coating agent in water by salification to
form an aqueous solution, dispersing the medicament particles first in
water, then in the solution of salified coating agent to form a
suspension, and adding an acidifying agent to precipitate the coating
agent onto the particles of medicament and recovering the microcapsules
thus formed.
U.S. Pat. No. 4,460,563, issued to Massimo Calanchi, discloses the
microencapsulation of ibuprofen with hydroxypropylmethylcellulose
phthalate.
U.S. Pat. Nos. 4,835,186; 4,835,187; and 4,835,188 are directed to making
taste-neutral (taste-masked) ibuprofen in dry powder form. U.S. Pat. Nos.
4,835,186 and U.S. Pat. No. 4,835,187 involve obtaining this taste-neutral
ibuprofen in powder form by spray drying suspensions of colloidal silica
in organic solvent solutions of ibuprofen and a cellulose material.
In U.S. Pat. No. 4,835,186, issued to Gerald L. Reuter et al, the organic
solvent is a mixture of lower alkanol, e.g., isopropanol, and ethyl
acetate, and the cellulose material is cellulose acetate phthalate. This
product is stated to contain about 40% to 70% by weight ibuprofen, about
15% to 50% by weight of cellulose acetate phthalate and about 5% to 40% by
weight colloidal silica.
In U.S. Pat. No. 4,835,187, issued to Gerald L. Reuter et al, the organic
solvent is a lower alkanol, e.g., isopropanol, or contains at least 50%
lower alkanol, and the cellulose material is ethyl cellulose, hydroxyethyl
cellulose, or hydroxypropylmethyl cellulose, alone or in admixture. The
lower alkanol solvent has a colloidal silica suspended therein. This
product is stated to contain about 40% to 70% by weight ibuprofen, about
15% to 50% of a cellulose material selected from the group consisting of
ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and
admixtures thereof and about 5% to 40% by weight colloidal silica.
In U.S. Pat. No. 4,835,188, issued to Ying T. R. Ho et al, the
taste-neutral powder form of ibuprofen is obtained by spray drying a
dispersion of ibuprofen and ethyl cellulose in water having a plasticizer
dissolved or suspended therein. This powder is stated to contain about 63%
to 77% by weight ibuprofen, about 25% to 40% by weight ethyl cellulose and
about 2% to 7% weight plasticizer.
An article by H. P. Merkle et al entitled "Preparation and In Vitro
Evaluation of Cellulose Acetate Phthalate Coacervate Microcapsules", J.
Pharm Science 62 pp. 1444-1448 (1973) describes the microencapsulation of
phenacetin by coacervation of aqueous cellulose acetate phthalate using
sodium sulfate as the coacervating agent. The article in column 1 on page
1444 refers to other literature describing coacervate encapsulation, a
common preparation technique being either simple coacervation of gelatin
with ethanol or sodium sulfate as dehydrating agents or complex
coacervation of gelatin acacia mixtures. The statement is made by the
authors that "Coacervation methods with pure gelatin and mixtures are
rather complicated and difficult to control, particularly with regard to
the hardening of the shells and the recovery of the microcapsules". In the
last complete paragraph in column 1 on page 1448, the authors refer to
other literature as showing an extremely rapid initial release from
gelatin coacervate microcapsules.
The present invention provides a method of simultaneously encapsulating
ibuprofen using both gelatin and cellulose acetate phthalate as the
encapsulating material to give the microcapsules a dual coating, the
gelatin portion of the coating providing high bioavailability of the
ibuprofen core and the cellulose acetate phthalate providing the
taste-masking effect. The gelatin in the dual coating serves to temper the
well known delayed release properties of the cellulose acetate phthalate
without interfering with its taste-masking function.
DETAILED DESCRIPTION OP THE INVENTION
This invention enables the preparation of individual taste-masked high
bioavailability microcapsules by microencapsulation of water-insoluble
NSAID drug materials in the substantial absence of microcapsule
agglomerates, viz., agglomerates of individual microcapsules. These
taste-masked highly bioavailable individual microcapsules can then be
formulated into chewable tablets and liquid aqueous suspensions of the
appropriate dosage for medicinal use. Both cellulose acetate phthalate and
gelatin are the microencapsulating polymer microcapsule wall materials.
Control of pH, controlled addition of a Hofmeister (lyotropic) salt,
simultaneous microencapsulation of the water-insoluble NSAID medicament
with a liquid phase of both cellulose acetate phthalate and gelatin
polymer material and the subsequent insolubilization of said liquid
microencapsulating material, after it has wrapped around the medicament
core, with glutaraldehyde and dilute acid are important process parameters
to achieving the proper individual microcapsules to obtain these highly
bioavailable, taste-masked water-insoluble NSAID drug materials by
microencapsulation alone. These individual microcapsules thus obtained are
bland tasting, however, and use of flavoring agents to impart pleasant
tastes to the already effectively taste-masked water-insoluble NSAID drug
materials is preferred when formulating same into chewable tablets and
liquid suspension oral dosage forms.
Usually the average/mean microcapsule diameter ranges from about 25 to
about 600 microns. The process of this invention involves the principal
steps of preparing an aqueous dispersion of the water-insoluble
non-steroidal, anti-inflammatory drug (NSAID) material within an aqueous
solution of cellulose acetate phthalate, said water-insoluble NSAID drug
material particles having a particle size ranging from about 25 to about
500 microns at a pH of about 6 or higher wherein said solution contains
from about 2 to about 8 wt. % of cellulose acetate phthalate; heating the
aqueous dispersion with agitation to a temperature sufficient to dissolve
gelatin; adding a solution of gelatin; gradually adding with continued
agitation a solution containing an inorganic Hofmeister (lyotropic) salt
to form both cellulose acetate phthalate and gelatin in liquid phase
separate from the equilibrium liquid; slowly lowering the temperature of
the dispersion to about 30.degree. C. then dropping the temperature
rapidly to about 15.degree. C.; gradually adding a solution of
glutaraldehyde; and after about 60 minutes slowly adjusting the pH of the
resulting solution by slow addition of a dilute acid to a pH of about 4 or
lower which renders said cellulose acetate phthalate polymer insoluble;
and recovering the individual microcapsules thus formed.
The term inorganic Hofmeister (lyotropic) salt as used herein refers to the
sulfate, citrate, tartrate, acetate, chloride, nitrate, bromide and iodide
anion salts of sodium, potassium, ammonium, rubidium, cesium, magnesium,
calcium, silicone, barium and lithium cations. Sodium sulfate is
preferred.
Various aldehydes can be used as cross-linking agents instead of
glutaraldehyde and these include, for example, formalin and acrolein.
While various dilute acids can be used to insolubilize the cellulose
acetate phthalate polymer cell wall material, e.g., citric acid, acetic
acid, fumaric acid, tartaric acid, etc., the use of citric acid is
preferred for this purpose in a concentration of about 10 to about 30 wt.
% in water.
Suitable water-insoluble NSAID drug materials which can be used in
accordance with this invention include, but are not necessarily limited
to, the following: naproxen, ibuprofen, sulindac, diclofenac, fenclofenac,
alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin,
acemetacin, fentiazac, clidanac, oxipinac, zomepirac sodium and
pharmaceutically acceptable water-insoluble salts thereof.
The taste-masked individual microcapsules of water-insoluble NSAID drug
material produced in accordance with this invention contain a high payload
of the water-insoluble NSAID drug core material, e.g., about 83+ wt. %,
based on total microcapsule weight.
The gelatin used in the invention can be of any origin so long as it is of
pharmaceutical grade. The gelatin, for example, can have a number average
molecular weight of about 27,000 to 70,000 with a Bloom number of about 55
to 325, an isoelectric point of about 5.0 to 9.2, and a viscosity of about
6 to 8 cps at 40.degree. C. The gelatin can be acid pretreated material
which has been deionized or alkali processed Hide gelatin, also deionized.
Preferably the gelatin is of USP or NF grade.
The relative amounts of gelatin and cellulose acetate phthalate used can
vary depending on the bioavailability and the degree of taste-masking
desired for the particular NSAID being encapsulated.
This invention will be illustrated in greater detail in the examples which
follow.
EXAMPLE 1
(Preparation of Cellulose Acetate Phthalate (CAP) and Gelatin
microencapsulated ibuprofen)
In a 2-liter beaker there are added 656 grams of deionized water. With
agitation, 9 grams of sodium bicarbonate were added to adjust the pH so as
to solubilize the cellulose acetate phthalate polymer. To this solution 35
grams of particulate cellulose acetate phthalate having a particle size of
about 14 mesh to 200 mesh, and more particularly about 1200 microns to
about 50 microns, were added in small increments with continued agitation
over 8-12 hours until all of the cellulose acetate phthalate (CAP) is
added and dissolved. The resulting solution contains 5 weight percent
cellulose acetate phthalate and has a pH of about 7.0 or slightly above.
To a 1500 ml beaker there were added 300 grams of the above CAP solution,
300 grams of deionized water, and 3 grams of a 5% aqueous solution of
sodium lauryl sulfate: Ibuprofen in the amount of 150 grams (sieved--30
mesh) was added slowly with stirring resulting in a pH of about 6 at
30.degree. C. The admixture was heated to 40.degree. with continued
stirring and then defoamed. To the admixture was then added 150 grams of a
10% aqueous Type A gelatin solution and the pH was about 6.2 at
372.degree. C.
With continued agitation, there were added slowly dropwise from a
separatory flask (250 ml) of a 20% by weight aqueous solution of sodium
sulfate over a period of 40-50 minutes. This sodium sulfate solution acts
as a coacervating agent permitting the gelatin and the cellulose acetate
phthalate polymer to come out as a liquid phase microencapsulating
material wrapping the drug particles. The dispersion temperature is then
allowed to drop slowly from 40.degree. C. to 30.degree. C. in 30-60
minutes and then the temperature is dropped quickly to 10.degree. C. The
pH of the mixture is then adjusted to 6.0 with 10% aqueous citric acid. At
this time 75 grams of a 25% glutaraldehyde solution is added to cross-link
the gelatin in the microcapsules and thus enable drying. The temperature
is raised to 20.degree. C. in one hour after the glutaraldehyde addition
and the pH of the dispersion is lowered to 3.5 by addition of a 10%
aqueous citric acid solution thereby rendering the cellulose acetate
phthalate and the gelatin insoluble at that pH. The microcapsule
dispersion is heated to 25.degree. C. in one hour and stirred overnight
(16-24 hours). The microcapsules are then allowed to settle and the
manufacturing medium is decanted. Fresh wash water in the amount of 1500
milliliters is then added and the microcapsule dispersion is stirred for
five minutes. The washing process is repeated three times and the
microcapsules are then vacuum filtered and dried in a tray dryer. The
microcapsules are sieved through a 20 mesh (840.mu.) screen and 9.2 grams
were oversize. The yield was 177.1 grams, or 97.4%. The microcapsules had
an ibuprofen payload of 83+ weight percent.
EXAMPLE 2
(Formulation of chewable tablets containing the CAP and gelatin
microencapsulated ibuprofen prepared according to Example 1)
The following materials are added in the following proportions to a
laboratory V-blender and blended for twenty minutes. The proportions are
for a 50 milligram (active) tablet.
______________________________________
mg/tab
______________________________________
Ibuprofen Gelatin/CAP microcaps
*
Mannitol Granules, USP
**
Aspartame, NF 10.0
Grape Flavor, Artificial
3.0
Citric Acid, Fine Granular USP
1.5
Crospovidone, NF 0.8
D&C Red #27 0.8
FD&C Blue #1 0.1
Talc 8.0
Colloidal Silicon Dioxide
6.0
Magnesium Stearate 2.5
325.
______________________________________
The tablet weight is fixed by allowing for variation in the amounts of
microcapsules and Mannitol Granules, USP used.
After blending the above materials for 20 minutes, a small portion of the
blend is removed into a container and magnesium stearate is added thereto.
The materials are mixed by hand and returned to the V-blender and blended
for 5-10 minutes.
Tablets are compressed from this mixture on a Stokes RB2 rotary press with
3/8 inch round, beveled edge, scored tooling. These tablets had
satisfactory hardness and friability.
The amount of ibuprofen gelatin/CAP microcapsules needed depends on the
active content or assay of the microcapsules. This amount can be
calculated with the following equation.
##EQU1##
The amount of Mannitol Granules, USP needed is equal 291.675
mg/tab--amount of microcapsules needed. Since this formula is dose
proportional, the desired active content can be obtained by multiplying
all ingredient amounts by the appropriate factor.
The active content or assay of the ibuprofen microcapsules of Example 1 is
83% by weight of microcapsule. Hence for 50 milligram active chewable
tablets, the amount of microcapsules in the above formulation is
##EQU2##
milligrams of ibuprofen gelatin/CAP microcaps and the amount of mannitol
granules required is
291.675-60.24=231.435 milligram
EXAMPLE 3
(Preparation of Cellulose Acetate Phthalate (CAP) and Gelatin
Microencapsulated Ibuprofen)
Into a 3-liter beaker fitted with a birdcage baffle and a stirring motor
with a 3" turbine blade, were added 90 grams of CAP into 1687 ml. of
deionized water. The batch was stirred overnight.
With agitation, 23 grams of sodium bicarbonate was added to adjust the pH
so as to solubilize the CAP. The CAP has a particle size of about 40 mesh
to 200 mesh. Three grams of sodium lauryl sulfate dissolved in 57 grams of
water were added with stirring and the CAP particles were well dispersed
to facilitate dissolving the CAP polymer. The resulting solution contains
5 wt. % CAP and has a pH of about 7.0 or slightly above.
Next, 500 g of ibuprofen were dispersed into the CAP solution. The
ibuprofen particles had a particle size of approximately 25 to 500
microns. As a defoamer, 5 grams of simethicone emulsion in 45 grams of
water was added and then 210 grams of gelatin Type A dissolved in 1890
grams of water (10% solution) were added with stirring.
The sodium sulfate solution comprising 860 grams of sodium sulfate
dissolved in 2440 grams of water (26% solution) was added slowly
(dropwise) with continuous agitation at about 150 rpm. This addition takes
place over approximately 1-1/2 hours. This sodium sulfate aqueous solution
acts as a coacervating agent permitting the CAP polymer and the gelatin to
come out as liquid phase microencapsulating materials wrapping the
ibuprofen drug particles. During the sodium sulfate addition the mixture
was slowly cooled from 40.RTM. C to 30.RTM. C and then fast cooled to
10.RTM.C.
After the CAP gelatin liquid microcapsule walls are formed, the CAP polymer
was rendered insoluble by slow addition of 500 grams of an 10% aqueous
citric acid solution until the final solution pH is approximately 4, thus
rendering the CAP insoluble at that pH for water. At this point a 50%
aqueous solution of glutaraldehyde in the amount of 52.5 milliliters was
added to cross-link the gelatin and the mixture was heated to 20.degree.
C. and then stirred overnight. Once this has been accomplished, the
agitation is stopped and the microcapsules are allowed to settle from
solution so that the supernatant liquid may be decanted.
These individual microcapsules of ibuprofen were then washed with 6
kilograms of water and washed four times more with 8 kilogram portions of
water. The washed CAP and gelatin walled microencapsulated ibuprofen
microcapsules were then filtered by a vacuum filter and dried using a
fluid bed dryer at a temperature of 30.degree. C. for a period of about
1-2 hours. These individual beige free flowing microcapsules contain
approximately 83 wt. % ibuprofen.
EXAMPLE 4
(Microencapsulation of naproxen with cellulose acetate phthalate (CAP)) and
gelatin.
Naproxen is microencapsulated with cellulose acetate phthalate and gelatin
using the same procedure and concentrations as set forth in Example 1
except that naproxen is used in place of ibuprofen. The naproxen
individual microcapsule core payload is approximately 83 wt. % with the
remainder being cellulose acetate phthalate and gelatin microcapsule wall
material.
EXAMPLE 5
(Preparation of a liquid suspension containing the Cap and gelatin
microencapsulated ibuprofen prepared according to Example 1)
The CAP and gelatin microencapsulated ibuprofen microcapsules prepared in
accordance with Example 1 above were then formulated into a liquid
suspension dosage form. The preparation of the liquid suspension dosage
form was accomplished as follows:
Four (4) liters of liquid suspension vehicle were prepared by the following
procedures:
All of the following ingredients were dry blended: grams of sucrose,
800 grams of sodium
20 grams of sodium carboxymethylcellulose,
4.8 grams of xanthan gum,
4.8 grams of sodium saccharin,
46.5 milligrams of FD&C Yellow #5, and
103.5 milligrams of FD&C Yellow #6
The above dry blended materials were then dissolved in approximately 1500
ml of purified water in a 4-liter beaker with agitation. Then 4.8 grams of
methyl paraben and 1.2 grams of propyl paraben were dissolved in 40 ml of
USP propylene glycol and added to the above water solution. Then the
following materials were added sequentially in their noted amounts:
1200 grams of light corn syrup,
8 ml of orange flavor oil,
2 grams of Tween 80, and
40 ml of a 20% (W/V) aqueous solution of citric acid.
All ingredients were allowed sufficient time to mix and then there was
added a sufficient quantity of purified water to bring the volume to 4
liters.
2.4 grams of the high payload (83%) CAP and gelatin microencapsulated
individual ibuprofen microcapsules prepared in accordance with Example 1
were added to 100 ml of the liquid suspension vehicle produced as
indicated above to form a liquid suspension dosage form of
microencapsulated ibuprofen.
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